1. Field of the Invention
The instant invention is related to the field of neuroactive peptides, proteins, or amino acid compositions.
2. Description of the Related Art
It is now well known that the central nervous system (CNS) of mammals employs many neuroactive peptides to effect speciallized signalling within the brain and spinal cord. Among the more well known neuroactive peptides are Somatostatin, Cholecystokinin, VIP, Substance P, Enkephalin, Neuropeptide Y (NPY), Neurotensin, TRH, CCK, and dynorphin. (see generally The Biochemical Basis of Neuropharmacology, Cooper, Bloom and Roth, 5th ed., Oxford University Press, New York, 1986). The careful elucidation of the complex signalling pathways which operate in the CNS requires the identification and characterization of specific neuroactive peptides and their particular properties, as well as the characterization and localization of specific neurologically significant receptors. Identification of agonists and antagonists of CNS receptors, whether partial, complete, coordinately acting, or independently acting, is useful in that the more that is known of specific neuroactive peptides, the greater the range of manipulations that can be conducted on CNS receptor proteins, and the behaviour of CNS receptor complexes. Significantly, the identification of unique agonists or antagonists allows for the fine characterization and localization of subsets of neuroactive receptors by their binding to these agonists or antagonists. By identifying neuroactive peptides, and using them to specifically perturb the behaviour of known receptor complexes, more detailed understanding becomes available about the receptor complex. In addition, new neuroactive peptides offer alternative means of altering the behaviour of known CNS receptor complexes, or for the discovery of previously unknown receptor complexes or unknown behavior of known receptors.
The N-methyl-D-aspartate (NMDA) receptor, which has been implicated in neurodegenerative disorders, stroke-related brain cell death, convulsive disorders, learning and memory, has been cloned from human tissue (see Hoffman, M., 1991, Science, 254:801-2). In addition to being activated by binding to NMDA, the NMDA receptors are activated by glutamate (Glu), and aspartate (Asp), as well as being competitively antagonized by D-2-amino-5-phosphonovalerate (D-AP5; D-APV), or non-competitively antagonized by phenylcyclidine (PCP), and MK-801. However, most interestingly, the NMDA receptor is coactivated by glycine (Gly). (Kozikowski et al., 1990, Journal of Medicinal Chemistry 33:1561-1571). The binding of glycine to an allosteric regulatory site on the NMDA receptor complex increases both the duration of channel open time, and most dramatically the frequency of the opening of the NMDA receptor channel.
The NMDA receptor is considered central to long-term potentiation (LTP), which is the persistent strengthening of neuronal connections that is considered to underlie learning and memory (see Bliss and Collingridge, 1993, Nature 361: 31-39, for review). Damage to the CNS, which may occur for example during a stroke, is thought to cause the overexcitement of cells which have the NMDA receptor by flooding of glutamate or aspartate, leading to the death of some 80% of such overexcited cells. The bulk of NMDA receptor carrying cells are in the cortex and hippocampus regions of the brain, and after such overexcited killing of cells, patients are rendered incapable of learning new things, but can still recall items in long term memory. Human memory deficits associated with PCP abuse have been linked to the action of PCP, and is an expected consequence of the inhibition of calcium fluxes through the NMDA receptor.
It is thought that drugs which can block, or otherwise alter the operation of the NMDA receptor may protect cells from overexcited killing, or NMDA receptor associated memory problems. Other drugs that interact with the NMDA receptor may enhance the ability of the cells to form LTP and thus enhance learning and memory.
Because of the significance of the NMDA receptor, it would be most useful to have specific peptide agonists or antagonists which will allow for fine mapping of the tissue distribution, subset characterization, and fine manipulation of NMDA receptors, and for characterization of the action of other agonists or antagonists on the NMDA receptor.